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Alzheimer's disease (AD) involves a complex pathophysiology with multiple interconnected subpathologies, including protein aggregation, impaired neurotransmission, oxidative stress, and microglia-mediated neuroinflammation. Current treatments, which generally target a single subpathology, have failed to modify the disease's progression, providing only temporary symptom relief. Multi-target drugs (MTDs) address several subpathologies, including impaired aggregation of pathological proteins. In this review, we cover hybrid molecules published between 2014 and 2024. We offer an overview of the strategies employed in drug design and approaches that have led to notable improvements and reduced hepatotoxicity. Our aim is to offer insights into the potential development of new Alzheimer's disease drugs. This overview highlights the potential of multi-target drugs featuring heterocycles with N-benzylpiperidine fragments and natural compounds in improving Alzheimer's disease treatment. [ABSTRACT FROM AUTHOR]

Introduction: Chronic cocaine exposure induces an increase in dopamine release and an increase in the expression of the Fos protein in the rat striatum. It has been suggested that both are necessary for the expression of cocaine-induced alterations in behavior and neural circuitry. Mirtazapine dosing attenuated the cocaine-induced psychomotor and reinforcer effects. Methods: The study evaluates the effect of chronic dosing of mirtazapine on cocaine-induced extracellular dopamine levels and Fos protein expression in rats. Male Wistar rats received cocaine (10 mg/Kg; i.p.) during the induction and expression of locomotor sensitization. The mirtazapine (30 mg/Kg; MIR), was administered 30 minutes before cocaine during the cocaine withdrawal. After each treatment, the locomotor activity was recorded for 30 minutes. Animals were sacrificed after treatment administration. Dopamine levels were determined by high-performance liquid chromatographic (HPLC) in the ventral striatum, the prefrontal cortex (PFC), and the ventral tegmental area (VTA) in animals treated with mirtazapine and cocaine. The quantification of c-fos immunoreactive cells was carried out by stereology analysis. Results: Mirtazapine generated a decrease in cocaine-induced locomotor activity. In addition, mirtazapine decreased the amount of cocaine-induced dopamine and the number of cells immunoreactive to the Fos protein in the striatum, PFC, and VTA. Discussion: These data suggest that mirtazapine could prevent the consolidation of changes in behavior and the cocaine-induced reorganization of neuronal circuits. It would explain the mirtazapine-induced effects on cocaine behavioral sensitization. Thus, these data together could support its possible use for the treatment of patients with cocaine use disorder. [ABSTRACT FROM AUTHOR]

Designed multi-target ligands (DMLs) that target multiple pathologies represent an emerging strategy in Alzheimer's disease (AD) research. DMLs are conceptualized to improve upon single-target therapies by potentially modifying multiple aspects of AD pathophysiology concurrently, a novel approach that reflects our evolving understanding of the disease. Innovations in genetic research and pharmacological development underpin the design of new multi-target drugs (MTDs) with the aim of achieving synergistic effects across various pathological processes implicated in AD. The complexities inherent in MTD design and development, such as optimizing target affinity, highlight the pressing need for continued innovation and collaboration across scientific disciplines. Alzheimer's disease (AD), a leading cause of dementia, increasingly challenges our healthcare systems and society. Traditional therapies aimed at single targets have fallen short owing to the complex, multifactorial nature of AD that necessitates simultaneous targeting of various disease mechanisms for clinical success. Therefore, targeting multiple pathologies at the same time could provide a synergistic therapeutic effect. The identification of new disease targets beyond the classical hallmarks of AD offers a fertile ground for the design of new multi-target drugs (MTDs), and building on existing compounds have the potential to yield in successful disease modifying therapies. This review discusses the evolving landscape of MTDs, focusing on their potential as AD therapeutics. Analysis of past and current trials of compounds with multi-target activity underscores the capacity of MTDs to offer synergistic therapeutic effects, and the flourishing genetic understanding of AD will inform and inspire the development of MTD-based AD therapies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), a chronic neurodegenerative disease, is clinically characterized by loss of memory and learning ability among other neurological deficits. Amyloid plaques, hyperphosphorylated tau protein, and neurofibrillary tangles involve in AD etiology. Meanwhile, enzymes and their inhibitors have become the focus of research in AD treatment. In this review, the molecular mechanisms involved in the pathogenesis of AD were overviewed and various enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase, γ-secretase, monoamine oxidase (MAO), and receptor of advanced glycation end products (RAGE) were highlighted as potential targets for AD treatment. Several hybrid molecules with essential substructures derived from various chemotypes have demonstrated desired pharmacological activity. It is envisioned that the development of new drugs that inhibit enzymes involved in AD is a future trend in the management of the disease.

Alzheimer’s disease (AD) is a major type of dementia and neurodegenerative disease, characterized by memory loss and cognitive decline. Over decades, significant efforts have been dedicated to finding its cause, pathogenic mechanisms, biomarkers for early detection, and clinical trials for its treatment. Earlier approved drugs mainly ameliorated the symptoms of AD, until recent years when two drugs targeting amyloid-beta (Aβ) protein were approved to slow down the progression of the disease. This review article encompasses the history of drug development in treating AD and clinical trials that failed and succeeded. Clinicaltrials.org website was systematically searched and screened for randomized controlled trials with results posted in the past 10 years. Among the 3,388 AD clinical trials, 211 interventional studies registered under AD have met eligibility. This review includes the interventional targets for drug discovery such as Aβ, tau, neurotransmitter receptors, neuroinflammation, multi-target studies, repurposing pharmacological agents, non-pharmacological interventions, and clinical therapy development for the neuropsychiatric symptoms of dementia. Current clinical trials are ongoing and no results are available as of yet. With the vast choices of drug targets that have been investigated, this review aims to present some insights into future AD drug design and trials and contribute to our ongoing efforts to find the cure.

Abstract Cancer is a major public health problem worldwide with more than an estimated 19.3 million new cases in 2020. The occurrence rises dramatically with age, and the overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective in older individuals. Conventional cancer treatments, such as radiotherapy, surgery, and chemotherapy, have been used for decades to combat cancer. However, the emergence of novel fields of cancer research has led to the exploration of innovative treatment approaches focused on immunotherapy, epigenetic therapy, targeted therapy, multi-omics, and also multi-target therapy. The hypothesis was based on that drugs designed to act against individual targets cannot usually battle multigenic diseases like cancer. Multi-target therapies, either in combination or sequential order, have been recommended to combat acquired and intrinsic resistance to anti-cancer treatments. Several studies focused on multi-targeting treatments due to their advantages include; overcoming clonal heterogeneity, lower risk of multi-drug resistance (MDR), decreased drug toxicity, and thereby lower side effects. In this study, we'll discuss about multi-target drugs, their benefits in improving cancer treatments, and recent advances in the field of multi-targeted drugs. Also, we will study the research that performed clinical trials using multi-target therapeutic agents for cancer treatment.

Cancer is a major public health problem worldwide with more than an estimated 19.3 million new cases in 2020. The occurrence rises dramatically with age, and the overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective in older individuals. Conventional cancer treatments, such as radiotherapy, surgery, and chemotherapy, have been used for decades to combat cancer. However, the emergence of novel fields of cancer research has led to the exploration of innovative treatment approaches focused on immunotherapy, epigenetic therapy, targeted therapy, multi-omics, and also multi-target therapy. The hypothesis was based on that drugs designed to act against individual targets cannot usually battle multigenic diseases like cancer. Multi-target therapies, either in combination or sequential order, have been recommended to combat acquired and intrinsic resistance to anti-cancer treatments. Several studies focused on multi-targeting treatments due to their advantages include; overcoming clonal heterogeneity, lower risk of multi-drug resistance (MDR), decreased drug toxicity, and thereby lower side effects. In this study, we'll discuss about multi-target drugs, their benefits in improving cancer treatments, and recent advances in the field of multi-targeted drugs. Also, we will study the research that performed clinical trials using multi-target therapeutic agents for cancer treatment. [ABSTRACT FROM AUTHOR]

IntroductionChronic cocaine exposure induces an increase in dopamine release and an increase in the expression of the Fos protein in the rat striatum. It has been suggested that both are necessary for the expression of cocaine-induced alterations in behavior and neural circuitry. Mirtazapine dosing attenuated the cocaine-induced psychomotor and reinforcer effects.MethodsThe study evaluates the effect of chronic dosing of mirtazapine on cocaine-induced extracellular dopamine levels and Fos protein expression in rats. Male Wistar rats received cocaine (10 mg/Kg; i.p.) during the induction and expression of locomotor sensitization. The mirtazapine (30 mg/Kg; MIR), was administered 30 minutes before cocaine during the cocaine withdrawal. After each treatment, the locomotor activity was recorded for 30 minutes. Animals were sacrificed after treatment administration. Dopamine levels were determined by high-performance liquid chromatographic (HPLC) in the ventral striatum, the prefrontal cortex (PFC), and the ventral tegmental area (VTA) in animals treated with mirtazapine and cocaine. The quantification of c-fos immunoreactive cells was carried out by stereology analysis. ResultsMirtazapine generated a decrease in cocaine-induced locomotor activity. In addition, mirtazapine decreased the amount of cocaine-induced dopamine and the number of cells immunoreactive to the Fos protein in the striatum, PFC, and VTA.DiscussionThese data suggest that mirtazapine could prevent the consolidation of changes in behavior and the cocaine-induced reorganization of neuronal circuits. It would explain the mirtazapine-induced effects on cocaine behavioral sensitization. Thus, these data together could support its possible use for the treatment of patients with cocaine use disorder.

Designing magic shotgun compounds, i.e., compounds hitting multiple targets using artificial intelligence (AI) systems based on machine learning (ML) and deep learning (DL) approaches, has a huge potential to revolutionize drug discovery. Such intelligent systems enable computers to create new chemical structures and predict their multi-target properties at a low cost and in a time-efficient manner. Most examples of AI applied to drug discovery are single-target oriented and there is still a lack of concise information regarding the application of this technology for the discovery of multi-target drugs or drugs with broad-spectrum action. In this review, we focus on current developments in AI systems for the next generation of automated design of multi-target drugs. We discuss how classical ML methods, cutting-edge generative models, and multi-task deep neural networks can help de novo design and hit-to-lead optimization of multi-target drugs. Moreover, we present state-of-the-art workflows and highlight some studies demonstrating encouraging experimental results, which pave the way for de novo drug design and multi-target drug discovery.

Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several of the synthesized compounds possess pronounced inhibitory activities against HDAC and COX isoforms. The membrane permeability and inhibition of cellular HDAC activity of selected compounds were confirmed by whole-cell HDAC inhibition assays and immunoblot experiments. The most promising dual inhibitors, C3 and C4, evoked antiproliferative effects in the low micromolar concentration range and caused a significant increase in apoptotic cells. In contrast to previous reports, the simultaneous inhibition of HDAC and COX activity by dual HDAC-COX inhibitors or combination treatments with vorinostat and celecoxib did not result in additive or synergistic anticancer activities. [ABSTRACT FROM AUTHOR]

The majority of research to combat SARS-CoV-2 infection exploits the adaptive immune system, but innate immunity, the first line of defense against pathogenic microbes, is equally important in understanding and controlling infectious diseases. Various cellular mechanisms provide physiochemical barriers to microbe infection in mucosal membranes and epithelia, with extracellular polysaccharides, particularly sulfated polysaccharides, being among the most widespread and potent extracellular and secreted molecules blocking and deactivating bacteria, fungi, and viruses. New research reveals that a range of polysaccharides effectively inhibits COV-2 infection of mammalian cells in culture. This review provides an overview of sulfated polysaccharides nomenclature, its significance as immunomodulators, antioxidants, antitumors, anticoagulants, antibacterial, and as potent antivirals. It summarizes current research on various interactions of sulfated polysaccharide with a range of viruses, including SARS-CoV-2, and their application for potential treatments for COVID-19. These molecules interact with biochemical signaling in immune cell responses, by actions in oxidative reactions, cytokine signaling, receptor binding, and through antiviral and antibacterial toxicity. These properties provide the potential for the development of novel therapeutic treatments for SARS-CoV-2 and other infectious diseases from modified polysaccharides.

Background: Drug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease. Methods: Here, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of in vitro (EC50 = 0.4 mM) and in vivo models, we show that methotrexate is able to inhibit COVID-19 via multiple mechanisms. Results: Our in vitro studies illustrate that methotrexate can suppress SARSCoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals. Conclusions: We demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials. [ABSTRACT FROM AUTHOR]

There is new and increasing evidence from in vitro, in vivo and clinical studies implicating the pivotal role of iron and associated metabolic pathways in the initiation, progression and development of cancer and in cancer metastasis. New metabolic and toxicity mechanisms and pathways, as well as genomic, transcription and other factors, have been linked to cancer and many are related to iron. Accordingly, a number of new targets for iron chelators have been identified and characterized in new anticancer strategies, in addition to the classical restriction of/reduction in iron supply, the inhibition of transferrin iron delivery, the inhibition of ribonucleotide reductase in DNA synthesis and high antioxidant potential. The new targets include the removal of excess iron from iron-laden macrophages, which affects anticancer activity; the modulation of ferroptosis; ferritin iron removal and the control of hyperferritinemia; the inhibition of hypoxia related to the role of hypoxia-inducible factor (HIF); modulation of the function of new molecular species such as STEAP4 metalloreductase and the metastasis suppressor N-MYC downstream-regulated gene-1 (NDRG1); modulation of the metabolic pathways of oxidative stress damage affecting mitochondrial function, etc. Many of these new, but also previously known associated iron metabolic pathways appear to affect all stages of cancer, as well as metastasis and drug resistance. Iron-chelating drugs and especially deferiprone (L1), has been shown in many recent studies to fulfill the role of multi-target anticancer drug linked to the above and also other iron targets, and has been proposed for phase II trials in cancer patients. In contrast, lipophilic chelators and their iron complexes are proposed for the induction of ferroptosis in some refractory or recurring tumors in drug resistance and metastasis where effective treatments are absent. There is a need to readdress cancer therapy and include therapeutic strategies targeting multifactorial processes, including the application of multi-targeting drugs involving iron chelators and iron–chelator complexes. New therapeutic protocols including drug combinations with L1 and other chelating drugs could increase anticancer activity, decrease drug resistance and metastasis, improve treatments, reduce toxicity and increase overall survival in cancer patients. [ABSTRACT FROM AUTHOR]

Despite the ever‐increasing number of available options for the treatment of epilepsies and the remarkable advances on the understanding of their pathophysiology, the proportion of refractory patients has remained approximately unmodified during the last 100 years. How efficient are we translating positive outcomes from basic research to clinical trials and/or the clinical scenario? It is possible that fresh thinking and exploration of new paradigms are required to arrive at truly novel therapeutic solutions, as seemingly proven by recently approved first‐in‐class antiseizure medications and drug candidates undergoing late clinical trials. Here, the author discusses some approximations in line with the network pharmacology philosophy, which may result in highly innovative (and, hopefully, safer and/or more efficacious) medications for the control of seizures, as embodied with some recent examples in the field, namely tailored multi‐target agents and low‐affinity ligands. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV–BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid β-peptide (Aβ) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aβ42 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 µM), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9−1.7 µM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1−58.7%) and Cu(II)-induced (40.3−60.8%) Aβ aggregation and also to narrow (22.4−42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Aβ42 and oxidative stress. Therefore, RIV–BIM hybrids seem to be potential drug candidates for AD with multi-target abilities. [ABSTRACT FROM AUTHOR]

Combination therapy is the standard of treatment for virtually all current non-communicable diseases, primarily chronic coronary heart disease, in modern terminology - "chronic coronary syndrome" (CSS), arterial hypertension, chronic heart failure, diabetes mellitus. The need for a combination of drugs increases even more with comorbidity, which is a typical situation in clinical practice. The recently accumulated material requires a review of the possibility of percutaneous coronary intervention and coronary bypass surgery in prolonging the life of patients with CCS, focusing on providing optimal medical therapy (OMT) for each patient with CCS, based on long-term treatment with antiplatelet agents, statins, angiotensin converting enzyme in-hibitors/angiotensin receptor blockers, beta-blockers. OMT aimed at preventing cardiovascular events and relieving symptoms in patients with CCS requires maximum commitment - a key factor in achieving therapeutic goals. Insufficient adherence of patients to prescribed therapy and its absence are the main barriers to increasing the survival rate of patients with cardiovascular diseases in primary and secondary prevention in the Russian Federation, as evidenced by numerous registers. The desire of the doctor to individualize treatment, which inevitably complicates the use of drugs, pushes patient adherence to treatment into the background. As a result, the patient's lack of commitment to each of the pharmaceuticals destroys the applicability of the OMT concept. A great achievement of the current stage of development of clinical cardiology and the pharmaceutical industry is the ability to offer patients optimal single pill combinations (SPC) in terms of effectiveness, tolerability, drug interactions, and ease of use. The article substantiates the prospects for a successful solution of this key problem by using a new generation of SPC components belonging to different pharmacological groups. The combination of three components (lisinopril, amlodipine and rosuvastatin), each of which has pleiotropic effects, provides a multi-targeted effect with a single dose, with the possibility of individualization of therapy, which is provided by four dosage options within this SPC.

Aim: The aim of the study is to compare the efficacy and safety of monotherapy with a sequential immune checkpoint inhibitor (ICI) programmed cell death protein-1 (PD-1) and its combination with multi-target drug sorafenib after transcatheter arterial chemoembolization (TACE) for advanced hepatocellular carcinoma (HCC). Methods: We conducted a retrospective evaluation of patients with advanced HCC who had received sequential PD-1 sorafenib (duplex group, n = 25) or monotherapy PD-1 alone (PD-1 group, n = 41) after TACE during April 2018–September 2021. Propensity score matching (PSM) was applied to correct the selection bias, and 22 pairs were created. The objective response rate (ORR), duration of the overall response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events were analyzed for both groups. Results: After PSM, the median PFS (7.63 vs. 2.9 months; p = 0.0335) was significantly longer for the duplex group than for the PD-1 group. The median OS (21.63 vs. 16.43 months; p = 0.103) was longer for the duplex group than for the PD-1 group, albeit without any statistical difference. The CR rate, ORR, DCR, and PFS rates at the first, third, and sixth months were higher for the duplex group than for the PD-1 group, wherein the PFS rate of the third and sixth months were statistically different. The OS rates at the sixth, 12th, and 18th months were better for the duplex group than for the PD-1 group, while the 18th-month OS rate (54.5% vs. 33.9%, p = 0.030) were statistically different between them. The most common adverse events after TACE included liver function injury, leukocytopenia, and thrombocytopenia, albeit without any statistical differences between the groups. Cox regression analysis showed that sorafenib combined immunotherapy after TACE and the achieving of CR or PR during the treatment were independent factors affecting PFS. Moreover, CNLC stage-IIIa, TACE frequency ≤2, and achievement of CR or PR were independent influencing factors of OS. Conclusions: Sequential PD-1 combined with sorafenib therapy after TACE for advanced HCC treatment is safe and effective, especially for patients with good initial treatment response, to further improve the disease prognosis. [ABSTRACT FROM AUTHOR]

AimThe aim of the study is to compare the efficacy and safety of monotherapy with a sequential immune checkpoint inhibitor (ICI) programmed cell death protein-1 (PD-1) and its combination with multi-target drug sorafenib after transcatheter arterial chemoembolization (TACE) for advanced hepatocellular carcinoma (HCC).MethodsWe conducted a retrospective evaluation of patients with advanced HCC who had received sequential PD-1 sorafenib (duplex group, n = 25) or monotherapy PD-1 alone (PD-1 group, n = 41) after TACE during April 2018–September 2021. Propensity score matching (PSM) was applied to correct the selection bias, and 22 pairs were created. The objective response rate (ORR), duration of the overall response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events were analyzed for both groups.ResultsAfter PSM, the median PFS (7.63 vs. 2.9 months; p = 0.0335) was significantly longer for the duplex group than for the PD-1 group. The median OS (21.63 vs. 16.43 months; p = 0.103) was longer for the duplex group than for the PD-1 group, albeit without any statistical difference. The CR rate, ORR, DCR, and PFS rates at the first, third, and sixth months were higher for the duplex group than for the PD-1 group, wherein the PFS rate of the third and sixth months were statistically different. The OS rates at the sixth, 12th, and 18th months were better for the duplex group than for the PD-1 group, while the 18th-month OS rate (54.5% vs. 33.9%, p = 0.030) were statistically different between them. The most common adverse events after TACE included liver function injury, leukocytopenia, and thrombocytopenia, albeit without any statistical differences between the groups. Cox regression analysis showed that sorafenib combined immunotherapy after TACE and the achieving of CR or PR during the treatment were independent factors affecting PFS. Moreover, CNLC stage-IIIa, TACE frequency ≤2, and achievement of CR or PR were independent influencing factors of OS.ConclusionsSequential PD-1 combined with sorafenib therapy after TACE for advanced HCC treatment is safe and effective, especially for patients with good initial treatment response, to further improve the disease prognosis.

Xolani H Makhoba,1 Claudio Viegas Jr,2 Rebamang A Mosa,1 Flávia PD Viegas,2 Ofentse J Pooe3 1Department of Biochemistry, Genetics and Microbiology, Division of Biochemistry, University of Pretoria, Hatfield, South Africa; 2Laboratory of Research in Medicinal Chemistry (PeQuiM), Institute of Chemistry, Federal University of Alfenas, Alfenas, MG, Brazil; 3Discipline of Biochemistry, School of Life Sciences, University of KwaZulu-Natal, Durban, South AfricaCorrespondence: Xolani H MakhobaDepartment of Biochemistry, Genetics and Microbiology, Division of Biochemistry, University of Pretoria, Hatfield 2000, South AfricaTel +2712 4204149Email zolanimakhoba53@gmail.comOfentse J PooeDiscipline of Biochemistry, School of Life Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South AfricaTel +2731 2607664Email PooeO@ukzn.ac.zaAbstract: It is essential to acknowledge the efforts made thus far to manage or eliminate various disease burden faced by humankind. However, the rising global trends of the so-called incurable diseases continue to put pressure on Pharma industries and other drug discovery platforms. In the past, drugs with more than one target were deemed as undesirable options with interest being on the one-drug-single target. Despite the successes of the single-target drugs, it is currently beyond doubt that these drugs have limited efficacy against complex diseases in which the pathogenesis is dependent on a set of biochemical events and several bioreceptors operating concomitantly. Different approaches have thus been proposed to come up with effective drugs to combat even the complex diseases. In the past, the focus was on producing drugs from screening plant compounds; today, we talk about combination therapy and multi-targeting drugs. The multi-target drugs have recently attracted much attention as promising tools to fight against most challenging diseases, and thus a new research focus area. This review will discuss the potential impact of multi-target drug approach on various complex diseases with focus on malaria, tuberculosis (TB), diabetes and neurodegenerative diseases as the main representatives of multifactorial diseases. We will also discuss alternative ideas to solve the current problems bearing in mind the fourth industrial revolution on drug discovery.Keywords: multi-target drugs, malaria, diabetes, tuberculosis and drug discovery

Pursuing the widespread interest on multi-target drugs to combat Alzheimer´s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aβ aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aβ1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.

Control of diabetic complications including diabetic retinopathy involves suppression of multiple factors; hence the need for multi-target drugs is appreciable. Anti-inflammatory agents could have a dual effect on cancers, one by suppressing cancer mediating pathways, and by inhibiting aldose reductase enzyme (ALR2), proceeding with ALR2 inhibition related changes in curing cancers. 3D quantitative structure–activity relationship (QSAR) model was built based on the steric fields, hydrophobic and electrostatic fields using Field-Based QSAR which was used to predict the ALR2 inhibiting property of the phytocompounds, Eupalitin-3-O-galactoside, Picroside II, Agnuside and 7-O-Methylwogonin. All anti-inflammatory compounds had IC50 values in nanomolar concentrations, similar to the drug Epalrestat, indicating their capability to be used as multi target drugs in the future.

Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several of the synthesized compounds possess pronounced inhibitory activities against HDAC and COX isoforms. The membrane permeability and inhibition of cellular HDAC activity of selected compounds were confirmed by whole-cell HDAC inhibition assays and immunoblot experiments. The most promising dual inhibitors, C3 and C4, evoked antiproliferative effects in the low micromolar concentration range and caused a significant increase in apoptotic cells. In contrast to previous reports, the simultaneous inhibition of HDAC and COX activity by dual HDAC-COX inhibitors or combination treatments with vorinostat and celecoxib did not result in additive or synergistic anticancer activities.

Introduction: Chronic cocaine exposure induces an increase in dopamine release and an increase in the expression of the Fos protein in the rat striatum. It has been suggested that both are necessary for the expression of cocaine-induced alterations in behavior and neural circuitry. Mirtazapine dosing attenuated the cocaine-induced psychomotor and reinforcer effects., Methods: The study evaluates the effect of chronic dosing of mirtazapine on cocaine-induced extracellular dopamine levels and Fos protein expression in rats. Male Wistar rats received cocaine (10 mg/Kg; i.p.) during the induction and expression of locomotor sensitization. The mirtazapine (30 mg/Kg; MIR), was administered 30 minutes before cocaine during the cocaine withdrawal. After each treatment, the locomotor activity was recorded for 30 minutes. Animals were sacrificed after treatment administration. Dopamine levels were determined by high-performance liquid chromatographic (HPLC) in the ventral striatum, the prefrontal cortex (PFC), and the ventral tegmental area (VTA) in animals treated with mirtazapine and cocaine. The quantification of c-fos immunoreactive cells was carried out by stereology analysis., Results: Mirtazapine generated a decrease in cocaine-induced locomotor activity. In addition, mirtazapine decreased the amount of cocaine-induced dopamine and the number of cells immunoreactive to the Fos protein in the striatum, PFC, and VTA., Discussion: These data suggest that mirtazapine could prevent the consolidation of changes in behavior and the cocaine-induced reorganization of neuronal circuits. It would explain the mirtazapine-induced effects on cocaine behavioral sensitization. Thus, these data together could support its possible use for the treatment of patients with cocaine use disorder., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Barbosa-Méndez and Salazar-Juárez.)

The polygenic nature of Alzheimer's disease (AD) and cross-talk between several signaling cascades make it harder to decode the disease pathogenesis. β-secretase (BACE1) works upstream in the amyloidogenic processing of amyloid precursor protein (APP) to generate Aβ that rapidly aggregates to form fibrils, the most abundant component of plaques observed in AD brains. Here, we report dual inhibition of BACE1 and Aβ aggregation by neohesperidin, a flavonoid glycoconjugate, using multi-spectroscopic approaches, force microscopy, molecular modeling, and validated the potency in SH-SY5Y neuroblastoma cell lines. Steady-state and time-resolved fluorescence reveal that neohesperidin binds close to the catalytic aspartate dyad. This binding conformationally restricts the protein in closed form which possibly precludes APP recognition and thereby inhibits BACE1 activity. Neohesperidin also dose-dependently inhibits the amyloid fibril formation, as evident from ANS, ThT assay, and AFM. Neohesperidin ameliorates aggregated Aβ 25 – 35 induced ROS generation and mitochondrial dysfunction in the SH-SY5Y cell line. As a result, the amyloid induced apoptosis is significantly prohibited and normal neuronal morphology is rescued. These findings suggest neohesperidin as an inhibitor of the pathogenic conversion of Aβ to fibrillar amyloid assembly. Neohesperidin thus emerges as a non-toxic multi-potent scaffold for the development of AD therapeutics. • Neohesperidin inhibits both BACE1, Aβ aggregation. • Neohesperidin binding conformationally restricts BACE1. • Neohesperidin inhibits amyloid induced ROS generation and mitochondrial dysfunction. • Amyloid induced apoptosis is significantly prohibited by neohesperidin. • Neohesperidin inhibits pathogenic conversion of Aβ into fibrillar amyloid assembly. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV–BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid β-peptide (Aβ) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aβ42 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 µM), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9−1.7 µM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1−58.7%) and Cu(II)-induced (40.3−60.8%) Aβ aggregation and also to narrow (22.4−42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Aβ42 and oxidative stress. Therefore, RIV–BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.

Current antiretroviral therapies against HIV involve the usage of at least two drugs that target different stages of HIV life cycle. However, potential drug interactions and side effects pose a problem. A promising concept for complex disease treatment is 'one molecule‐multiple target' approach to overcome undesired effects of multiple drugs. Additionally, it is beneficial to consider drug re‐purposing due to the cost of taking a drug into the market. Taking these into account, here potential anti‐HIV compounds are suggested by virtually screening small approved drug molecules and clinical candidates. Initially, binary QSAR models are used to predict the therapeutic activity of around 7900 compounds against HIV and to predict the toxicity of molecules with high therapeutic activities. Selected compounds are considered for molecular docking studies against two targets, HIV‐1 protease enzyme, and chemokine co‐receptor CCR5. The top docking poses for all 549 molecules are then subjected to short (1 ns) individual molecular dynamics (MD) simulations and they are ranked based on their calculated relative binding free energies. Finally, 25 molecules are selected for long (200 ns) MD simulations, and 5 molecules are suggested as promising multi‐target HIV agents. The results of this study may open new avenues for the designing of new dual HIV‐1 inhibitor scaffolds. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common forms of dementia among elder people, which is a progressive neurodegenerative disease that results from a chronic loss of cognitive activities. It has been observed that AD is multifactorial, hence diverse pharmacological targets that could be followed for the treatment of AD. The Food and Drug Administration has approved two types of medications for AD treatment such as cholinesterase inhibitors (ChEIs) and N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Rivastigmine, donepezil, and galantamine are the ChEIs that have been approved to treat AD. On the other hand, memantine is the only non-competitive NMDAR antagonist approved in AD treatment. As compared with placebo, it has been revealed through clinical studies that many single-target therapies are unsuccessful to treat multifactorial Alzheimer's symptoms or disease progression. Therefore, due to the complex nature of AD pathophysiology, diverse pharmacological targets can be hunted. In this article, based on the entwined link of acetylcholinesterase (AChE) and NMDAR, we represent several multifunctional compounds in the rational design of new potential AD medications. This review focus on the significance of privileged scaffolds in the generation of the multi-target lead compound for treating AD, investigating the idea and challenges of multi-target drug design. Furthermore, the most auspicious elementary units for designing as well as synthesizing hybrid drugs are demonstrated as pharmacological probes in the rational design of new potential AD therapeutics. [ABSTRACT FROM AUTHOR]

Abstract Diseases of infection, of neurodegeneration (such as Alzheimer’s and Parkinson’s diseases), and of malignancy (cancers) have complex and varied causative factors. Modern drug discovery has the power to identify potential modulators for multiple targets from millions of compounds. Computational approaches allow the determination of the association of each compound with its target before chemical synthesis and biological testing is done. These approaches depend on the prior identification of clinically and biologically validated targets. This Perspective will focus on the molecular and computational approaches that underpin drug design by medicinal chemists to promote understanding and collaboration with clinical scientists.

Inhibition of more than one cancer‐related pathway by multi‐target agents is an emerging approach in modern anticancer drug discovery. Here, based on the well‐established synergy between histone deacetylase inhibitors (HDACi) and alkylating agents, we present the discovery of a series of alkylating HDACi using a pharmacophore‐linking strategy. For the parallel synthesis of the target compounds, we developed an efficient solid‐phase‐supported protocol using hydroxamic acids immobilized on resins (HAIRs) as stable and versatile building blocks for the preparation of functionalized HDACi. The most promising compound, 3 n, was significantly more active in apoptosis induction, activation of caspase 3/7, and formation of DNA damage (γ‐H2AX) than the sum of the activities of either active principle alone. Furthermore, to demonstrate the utility of our preloaded resins, the HAIR approach was successfully extended to the synthesis of a proof‐of‐concept proteolysis‐targeting chimera (PROTAC), which efficiently degrades histone deacetylases. [ABSTRACT FROM AUTHOR]

Pursuing the widespread interest on multi-target drugs to combat Alzheimer´s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aβ aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aβ1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy. Design, synthesis and evaluation of new tacrine-benzofuran hybrids as multitargeting anti- Alzheimer's disease agents; high AChE inhibition associated with other relevant properties; structure–activity relationship analysis [ABSTRACT FROM AUTHOR]

The process of bone metabolism includes catabolism of old or mature bone and anabolism of new bone, carried out by osteoclasts and osteoblasts respectively. Any imbalance in this process results in loss of bone mass or osteoporosis. Drugs available to combat osteoporosis have certain adverse effects and are unable to improve bone formation, hence identifying new agents to fulfil these therapeutic gaps is required. To expand the scope of potential agents that enhance bone formation, we identified Euonymus spraguei Hayata as a plant material that possesses robust osteogenic potential using human osteoblast cells. We isolated three compounds, syringaresinol (1), syringin (2), and (−)-epicatechin (3), from E. spraguei. Results demonstrated that syringin (2), and (−)-epicatechin (3), increased alkaline phosphatase activity significantly up to 131.01% and 130.67%, respectively; they also elevated mineral deposition with respective values of up to 139.39% and 138.33%. In addition, 2 and 3 modulated autophagy and the bone morphogenetic protein (BMP)-2 signaling pathway. Our findings demonstrated that 2 and 3 induced osteogenesis by targeting multiple pathways and therefore can be considered as potent multi-targeted drugs for bone formation against osteoporosis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has a complex pathophysiology that includes aggregation of pathological proteins, impaired neurotransmission, increased oxidative stress, or microglia-mediated neuroinflammation. Therapeutics targeting only one of these AD-related subpathologies have not yet been successful in the search for a disease-modifying treatment. Therefore, multi-target drugs (MTDs) aiming simultaneously at several subpathologies are expected to be a better approach. However, the concept of MTD is inherently connected with several limitations, which are often ignored during MTD design and development. Here, we provide an overview of the MTD approach and discuss its potential pitfalls in the context of AD treatment. We also put forward ideas to be used in the rational design of MTDs to obtain drugs that are effective against AD. AD has a complex pathophysiology comprising many intertwined subpathologies, such as impaired neurotransmission or distinct aggregated proteins. AD starts ~20 years before the first symptoms of dementia occur, and current treatment brings only modest and temporary relief from the symptoms but is not able to stop or slow down the progression of the disease. MTDs aim at different targets within the pathophysiology of the disease to achieve therapeutic synergy and, thus, are considered advantageous for AD treatment. The design of currently developed MTDs suffers several limitations, hampering their clinical utility. [ABSTRACT FROM AUTHOR]

Ten acridones isolated from Atalantia monophylla were evaluated for effects on Alzheimer’s disease pathogenesis including antioxidant effects, acetylcholinesterase (AChE) inhibition, prevention of beta-amyloid (Aβ) aggregation and neuroprotection. To understand the mechanism, the type of AChE inhibition was investigated in vitro and binding interactions between acridones and AChE or Aβ were explored in silico. Drug-likeness and ADMET parameters were predicted in silico using SwissADME and pKCSM programs, respectively. All acridones showed favorable drug-likeness and possessed multifunctional activities targeting AChE function, Aβ aggregation and oxidation. All acridones inhibited AChE in a mixed-type manner and bound AChE at both catalytic anionic and peripheral anionic sites. In silico analysis showed that acridones interfered with Aβ aggregation by interacting at the central hydrophobic core, C-terminal hydrophobic region, and the key residues 41 and 42. Citrusinine II showed potent multifunctional action with the best ADMET profile and could alleviate neuronal cell damage induced by hydrogen peroxide and Aβ1-42 toxicity.

A number of proteins contributing in pathogen's virulence mechanisms offer a potential target for anticandidal therapeutics. CPH1 and its regulatory proteins Cst20, Hst7, Cek1 (MAPK cascade) administers filamentation and morphogenesis in human pathogenic fungus Candida albicans. These proteins are essential targets for their involvement in the successful establishment of the fungi within the host. In silico drug design using virtual screening, docking and (ADME)/Tox analysis for identification of lead compounds is an economic strategy for the development of potent anticandidal agent. The study divulged five persuasive ligands (2-O-prenyl coumaric acid, 2-nitro-4-methyl-cinnamaldehyde, 3,5-diprenyl-4-coumaric acid, VT1161, T-2307) out of 25, which collectively inhibited Cst20, Hst7, Cek1 in C. albicans. They can hence be used as natural drug leads for designing more effective inhibitors of multiple targets for C. albicans survival and progression of the disease. This study will enhance our understanding of the phenomenon "multiple targeting" and multi-target drug discovery further accelerating efficient broad-spectrum antifungal therapeutics development in near future. This study provides a good platform to eradicate the issue of "target shortage" that might facilitate the discovery of novel drugs in near future because the prolonged use of antibiotics over the years has transformed pathogenic fungus into resistant to many drugs. [ABSTRACT FROM AUTHOR]

Abstract Complex diseases (e.g., Alzheimer's disease) or infectious diseases are usually caused by complicated and varied factors, including environmental and genetic factors. Multi-target (polypharmacology) drugs have been suggested and have emerged as powerful and promising alternative paradigms in modern medicinal chemistry for the development of versatile chemotherapeutic agents to solve these medical challenges. The multifunctional agents capable of modulating multiple biological targets simultaneously display great advantages of higher efficacy, improved safety profile, and simpler administration compared to single-targeted agents. Therefore, multifunctional agents would certainly open novel avenues to rationally design the next generation of more effective but less toxic therapeutic agents. Herein, the authors review the recent progress made in the discovery and design processes of selective multi-targeted agents, especially the successful application of multi-target drugs for the treatment of Alzheimer's disease. Graphical abstract Multi-garget drugs with a high potency and selectivity toward multiple biological targets represent a novel and efficient drug discovery paradigm. The development of multi-target drugs generally contains several main steps such as target identification and validation, hits identification, and lead component optimization. It is believed that the multifunctional drugs would be more effective for the treatment of t complex diseases such as cancer and central nervous system diseases, which may require complex therapeutic approaches. Image 1 Highlights • It is shifting from the single- to multi-target drug, which is promising for combatting the complicated diseases. • Target identification is the first and critical step for multi-target drug discovery pipeline. • Rational design is the core for the development of multi-target agents involving various efficient methods. • Great progress has been made on multi-target drugs for the treatment of AD, which has been proved of clinical value. [ABSTRACT FROM AUTHOR]

Caffeoylquinic acids (CQA) are polyphenolic compounds found in fruits, vegetables, coffee, and spices that have exhibited several beneficial activities, including antioxidant, antibacterial, neuroprotective, anti-inflammatory, anticancer, antiviral, antidiabetic, and cardiovascular effects. A derivative, TCQA (3,4,5-Tri-O-caffeoylquinic acid), has also shown both neurogenic and pigment differentiation potential. A transcriptomic-based meta-analysis was conducted to explore potential biochemical processes and molecular targets of TCQA. This approach involved integrating data from various cell and tissue types, including human amniotic stem cells, human neural stem cells, human dermal papilla cells, and the brain cortex of aging model mice. It offered a comprehensive perspective on the significant gene regulations in response to TCQA treatment. The objective was to uncover the mechanism and novel targets of TCQA, facilitating a further understanding of its functions. New areas of interest found were TCQA's effect on adipogenesis, heart, and muscle tissue development. In addition, significantly enhanced biological activities found through meta-analysis included cell cycle, VEGFA-VEGFR2 pathway, and BMP signaling. Overall, a comprehensive functional and visual analysis using available biological databases uncovered the multi-target potential of this natural compound. [Display omitted] [ABSTRACT FROM AUTHOR]

Diabetes Mellitus (DM) is a multi-factorial chronic health condition that affects a large part of population and according to the World Health Organization (WHO) the number of adults living with diabetes is expected to increase. Since type 2 diabetes mellitus (T2DM) is suffered by the majority of diabetic patients (around 90–95%) and often the mono-target therapy fails in managing blood glucose levels and the other comorbidities, this review focuses on the potential drugs acting on multi-targets involved in the treatment of this type of diabetes. In particular, the review considers the main systems directly involved in T2DM or involved in diabetes comorbidities. Agonists acting on incretin, glucagon systems, as well as on peroxisome proliferation activated receptors are considered. Inhibitors which target either aldose reductase and tyrosine phosphatase 1B or sodium glucose transporters 1 and 2 are taken into account. Moreover, with a view at the multi-target approaches for T2DM some phytocomplexes are also discussed.

For every lead compound developed in medicinal chemistry research, numerous other inactive or less active candidates are synthetized/isolated and tested. The majority of these compounds will not be selected for further development due to a sub-optimal pharmacological profile. However, some poorly active or even inactive compounds could live a second life if tested against other targets. Thus, new therapeutic opportunities could emerge and synergistic activities could be identified and exploited for existing compounds by sharing information between researchers who are working on different targets. The Mu.Ta.Lig (Multi-Target Ligand) Chemotheca database aims to offer such opportunities by facilitating information exchange among researchers worldwide. After a preliminary registration, users can (a) virtually upload structures and activity data for their compounds with corresponding, and eventually known activity data, and (b) search for other available compounds uploaded by the users community. Each piece of information about given compounds is owned by the user who initially uploaded it and multiple ownership is possible (this occurs if different users uploaded the same compounds or information pertaining to the same compounds). A web-based graphical user interface has been developed to assist compound uploading, compounds searching and data retrieval. Physico-chemical and ADME properties as well as substructure-based PAINS evaluations are computed on the fly for each uploaded compound. Samples of compounds that match a set of search criteria and additional data on these compounds could be requested directly from their owners with no mediation by the Mu.Ta.Lig Chemotheca team. Guest access provides a simplified search interface to retrieve only basic information such as compound IDs and related 2D or 3D chemical structures. Moreover, some compounds can be hidden to Guest users according to an owner's decision. In contrast, registered users have full access to all of the Chemotheca data including the permission to upload new compounds and/or update experimental/theoretical data (e.g., activities against new targets tested) related to already stored compounds. In order to facilitate scientific collaborations, all available data are connected to the corresponding owner's email address (available for registered users only). The Chemotheca web site is accessible at http://chemotheca.unicz.it.

Objectives: Systems biology is a novel subject in the field of life science that aims at a systems’ level understanding of biological systems. Because of the significant progress in high-throughput technologies and molecular biology, systems biology occupies an important place in research during the post-genome era. Methods: The characteristics of systems biology and its applicability to traditional medicine research have been discussed from three points of view: data and databases, network analysis and inference, and modeling and systems prediction. Results: The existing databases are mostly associated with medicinal herbs and their activities, but new databases reflecting clinical situations and platforms to extract, visualize and analyze data easily need to be constructed. Network pharmacology is a key element of systems biology, so addressing the multi-component, multi-target aspect of pharmacology is important. Studies of network pharmacology highlight the drug target network and network target. Mathematical modeling and simulation are just in their infancy, but mathematical modeling of dynamic biological processes is a central aspect of systems biology. Computational simulations allow structured systems and their functional properties to be understood and the effects of herbal medicines in clinical situations to be predicted. Conclusion: Systems biology based on a holistic approach is a pivotal research methodology for understanding the mechanisms of traditional medicine. If systems biology is to be incorporated into traditional medicine, computational technologies and holistic insights need to be integrated.

publisher‐imprint‐name Springer volume‐issue‐count 1 issue‐article‐count 0 issue‐toc‐levels 0 issue‐pricelist‐year 2018 issue‐copyright‐holder The Author(s) issue‐copyright‐year 2018 article‐contains‐esm No article‐numbering‐style Unnumbered article‐registration‐date‐year 2017 article‐registration‐date‐month 12 article‐registration‐date‐day 30 article‐toc‐levels 0 toc‐levels 0 volume‐type Regular journal‐product ArchiveJournal numbering‐style Unnumbered article‐grants‐type OpenChoice metadata‐grant OpenAccess abstract‐grant OpenAccess bodypdf‐grant OpenAccess bodyhtml‐grant OpenAccess bibliography‐grant OpenAccess esm‐grant OpenAccess online‐first false pdf‐file‐reference BodyRef/PDF/40169_2017_Article_181.pdf target‐type OnlinePDF issue‐type Regular article‐type OriginalPaper journal‐subject‐primary Medicine & Public Health journal‐subject‐secondary Medicine/Public Health, general journal‐subject‐collection SC11 open‐access true --> Diseases of infection, of neurodegeneration (such as Alzheimer's and Parkinson's diseases), and of malignancy (cancers) have complex and varied causative factors. Modern drug discovery has the power to identify potential modulators for multiple targets from millions of compounds. Computational approaches allow the determination of the association of each compound with its target before chemical synthesis and biological testing is done. These approaches depend on the prior identification of clinically and biologically validated targets. This Perspective will focus on the molecular and computational approaches that underpin drug design by medicinal chemists to promote understanding and collaboration with clinical scientists. [ABSTRACT FROM AUTHOR]

HIV infection still has a serious health and socio-economical impact and is one of the primary causes of morbidity and mortality all over the world. HIV infection and the AIDS pandemic are still matters of great concern, especially in less developed countries where the access to highly active antiretroviral therapy (HAART) is limited. Patient compliance is another serious drawback. Nowadays, HAART is the treatment of choice although it is not the panacea. Despite the fact that it suppresses viral replication at undetectable viral loads and prevents progression of HIV infection into AIDS HAART has several pitfalls, namely, long-term side-effects, drug resistance development, emergence of drug-resistant viruses, low compliance and the intolerance of some patients to these drugs. Moreover, another serious health concern is the event of co-infection with more than one pathogen at the same time (e.g. HIV and HCV, HBV, herpes viruses, etc). Currently, the multi-target drug approach has become an exciting strategy to address complex diseases and overcome drug resistance development. Such multifunctional molecules combine in their structure pharmacophores that may simultaneously interfere with multiple targets and their use may eventually be more safe and efficacious than that involving a mixture of separate molecules because of avoidance or delay of drug resistance, lower incidence of unwanted drug-drug interactions and improved compliance. In this review we focus on multifunctional molecules with dual activity against different targets of the HIV life cycle or able to block replication, not only of HIV but also of other viruses that are often co-pathogens of HIV. The different approaches are documented by selected examples. [ABSTRACT FROM AUTHOR]